EP1177191A1 - Substituted benzimidazole, the production thereof and the use thereof as means against parasitic protozoa - Google Patents

Abstract

The present invention relates to novel substituted benzimidazoles, the production thereof and the use thereof as means against parasitic protozoa.

Description

Substituted benzimidazoles, their preparation and their use as agents against parasitic protozoa

The present invention relates to new substituted benzimidazoles, their preparation and their use as agents against parasitic protozoa.

The present invention further relates to mixtures of these compounds with polyether antibiotics or synthetically produced coccidiosis agents in agents for combating parasitic protozoa, in particular coccidia.

Substituted benzimidazoles and their use as insecticides, fungicides and herbicides have already been disclosed (EP-OS 87 375, 152 360, 181 826, 239 508, 260 744, 266 984, US Pat. No. 3,418,318, 3,472,865, 3,576 818, 3 728 994).

Halogenated benzimidazoles and their effects as anthelmintics, coccidiostatics and pesticides have become known (DE-OS 2 047 369, DE-OS 4 237 617). Mixtures of nitro-substituted benzimidazoles and polyether antibiotics have become known as coccidiosis agents (US Pat. No. 5,331,003). In all cases, their effects are not yet satisfactory.

Coccidiosis is a disease caused by unicellular parasites (protozoa). It can cause large losses, particularly in poultry farming. To avoid this, the stocks are treated prophylactically with coccidiosis. By developing resistance to the used

Funds have serious problems shortly after the funds are introduced. On the other hand, the use of chemically completely new coccidiosis agents, especially combinations, makes it possible to control polyresistant parasite strains.

New benzimidazoles of the formula (I)

in which

R ^{1 represents} fluoroalkyl,

R ^{2 represents} hydrogen or alkyl,

R ^{3 represents} alkyl,

X ¹ , X ² , X ³ and X ⁴ independently of one another represent hydrogen, halogen, haloalkyl, haloalkoxy, haloalkylthio or haloalkylsulfonyl,

or

X ² and X ³ or X ³ and X ⁴ together represent a dioxyhaloalkylene,

found that show excellent effectiveness against coccidiosis.

The benzimidazoles of the formula (I)

in which

R ¹ , R ² , R ³ , X ¹ to X ^{4 have} the meanings given above,

are made by

1 H-benzimidazoles of the formula (II)

in which

Rl and X ¹ to X ^{4 have} the meaning given above,

with an alkylating agent of formula (III)

in which

A stands for a suitable leaving group,

R ² and R ^{3 have} the meaning given above,

if appropriate in the presence of diluents and / or reaction auxiliaries.

Depending on the type and number of the substituents, the compounds of the formers (I) can optionally be present as geometric and / or optical isomers or regioisomers or their isomer mixtures in different compositions. Both the pure isomers and the isomer mixtures are claimed according to the invention.

The substituted benzimidazoles according to the invention are generally defined by the formula (I). Compounds of formula (I) are preferred in which

R ^{1 represents} C, -C ₄ fluoroalkyl,

R ^{2 represents} hydrogen or C, -C ₄ alkyl,

R ^{3 represents} C, -C ₄ alkyl. X ¹ , X ² , X ³ and X ⁴ independently of one another are hydrogen, F, Cl, Br, C j -C haloalkyl, C] -C haloalkoxy, C j -C haloalkylthio, C _j -C ₄ haloalkylsulfonyl stands,

X ² and X ³ or X ³ and X ⁴ can also be used together for a dioxyhalo

C i -C -alkylene radical.

Compounds of the formula (I) in which

R ^{1 stands} for CF ₃ , CHF ₂ , CHF,

R ^{2 represents} hydrogen, methyl, ethyl, n-propyl or isopropyl,

R ^{3 represents} methyl, ethyl, n-propyl or isopropyl,

X ¹ , X ² , X ³ and X ⁴ independently of one another for hydrogen. F, Cl, Br, CF ₃ , CHF ₂ ,

CH ₂ F, OCF ₃ , OCH ₂ F, OCHF ₂ , SCF ₃ , SCHF ₂ , SCH ₂ F, SO ₂ CF ₃ , SO ₂ CHF ₂ ,

SO ₂ CH ₂ F stands, whereby

X ² and X ³ or X ³ and X ⁴ also together for a radical -O-CF ₂ -0-,

-O-CF ₂ -CF ₂ -O-, -O-CF ₂ -CF ₂ -CF ₂ -O-, -O-CF ₂ -CHF-O-, -O-CC1F-CC1F-O-, -O -CHF-O-, -O-CHF-CHF-O- or -O-CC1F-O-.

Compounds of the formula (I) in which

R ^" > stands for -CF ₃ or -CHF ₂ ,

R ^{2 represents} hydrogen,

R ^{3 represents} methvl, X ^{1 represents} hydrogen, -CF ₃ , Cl, Br, F or -SCF ₃ ,

X ^{2 represents} hydrogen, -OCF ₃ , F, Br, Cl or CF ₃ ,

X ^{3 represents} F, Br, Cl, -OCF ₃ , -CF ₃ or -SO ₂ CF ₃ ,

X ^{4 represents} hydrogen, where

X ² and X ³ or X ³ and X ^{4 can} also be -OCF ₂ -CFHO-, -O-CC1F-CC1F-O-, -OCF ₂ -CF ₂ -O- or -O-CF ₂ -O- .

If, for example, 4-bromo-2,6-bis-trifluoromethylbenzimidazole is used to carry out the process according to the invention for the preparation of compounds of the formula (I), the course of the reaction of the preparation process can be represented by the following formula:

Formula (II) provides a general definition of the 1H-benzimidazoles required as starting materials for carrying out the production process. In this formula (II) R to R ³ and X ¹ to X ⁴ preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the compounds of the formula (I) according to the invention.

The IH-benzimidazoles of formula (II) are known or can be obtained in analogy to known processes (see, e.g., J. Amer. Chem. Soc. 75, 1292 [1953] US Patent 3,576,818).

Formula (III) provides a general definition of the alkylating agents which are furthermore required as starting products for carrying out the production process. In this formula (III) R ^ and R-> preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the substances of the formula (I) according to the invention.

A stands for a leaving radical customary in alkylating agents, preferably for

Halogen, in particular for chlorine, bromine or iodine or for optionally substituted alkylsulfonyloxy, alkoxysulfonyloxy or arylsulfonyloxy, such as in particular methanesulfonyloxy, trifluoromethanesulfonyloxy, methoxysulfonyloxy, ethoxysulfonyloxy or p-toluenesulfonyloxy.

The compounds of the formula (III) are generally known or can be obtained in analogy to known processes (see, for example, JP 58152879 [CA 100: 121042]; US 4,434,173; US 4,448,732).

Inert organic solvents are suitable as diluents for carrying out the production process. These include in particular aliphatic. alicyclic or aromatic, optionally halogenated hydrocarbons, such as gasoline, benzene. Toluene, xylene, chlorobenzene, dichlorobenzene. Petroleum ether. Hexane, cyclohexane, dichloromethane, chloroform or carbon tetrachloride; Ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl or diethyl ether; Ketones, such as acetone, butanone or methyl isobutyl ke- volume; Nitriles such as acetonitrile, propionitrile or benzonitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; Esters such as methyl acetate or ethyl acetate or bases such as pyridine or organic acids such as formic acid or acetic acid.

The production process is preferably carried out in the presence of a suitable reaction auxiliary. All conventional inorganic or organic bases are suitable as such. These include, for example, alkaline earth metal or alkali metal hydrides, hydroxides, amides, alcoholates, acetates, carbonates or hydrogen carbonates, such as sodium hydride, sodium amide, lithium diethylamide, sodium methylate, sodium ethylate, potassium tert. -butylate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium acetate, potassium acetate, calcium acetate, ammonium acetate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate or ammonium carbonate, organic lithium compounds such as n-butyllithium and tertiary amines such as trimethylamine, triethylamine , Tributylamine, diisopropylethylamine, tetramethylguanidine, N, N-dimethylaniline, pyridine, piperidine, N-methylpiperidine, N, N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclonones (DBN) or diazabicycloundecene (DBU).

The preparation process can optionally also be carried out in a two-phase system, such as water / toluene or water / dichloromethane, if appropriate in the presence of a suitable phase transfer catalyst. Examples of such catalysts are: tetrabutylammonium iodide, tetra-butylammonium bromide, tetrabutylammonium chloride, tributyl-methylphosphonium bromide, trimethyl-Ci 3 / Ci5-alkylammonium chloride, trimethyl-C ^ / C] 5-alkylammonium bromide, dibenzylmethylsulfonate, dibenzylmethylsulfonate Dimethyl-C j 2 C 14 -alky 1-benzylammonium chloride, dimethyl-C \ 2 / C] 4-alky 1-benzylammonium bromide. Tetrabutylammonium hydroxide, triethylbenzylammonium chloride, methyltrioctylammonium chloride, trimethylbenzylammonium chloride, 15-crown-5, 18-crown-6 or

Tris- [2- (2-methoxyethoxy) ethyl] amine. The reaction temperatures can be varied within a substantial range when carrying out the production process. In general, temperatures between -70 ° C and + 200 ° C, preferably at temperatures between 0 ° C and 130 ° C.

The manufacturing process is usually carried out under normal pressure. However, it is also possible to work under increased or reduced pressure.

To carry out the manufacturing process, 1H-

Benzimidazole of formula (II) generally 1.0 to 5.0 mol, preferably 1.0 to 2.5 mol of alkylating agent of formula (III) and optionally 0.01 to 5.0 mol, preferably 1.0 to 3.0 Mole of reaction auxiliary.

The reaction is carried out, worked up and isolated by known processes (see also the preparation examples).

The end products of the formula (I) are purified using customary methods, for example by column chromatography or by recrystallization.

The characterization takes place with the help of the melting point or with non-crystallizing compounds - in particular with regioisomer mixtures - with the help of proton nuclear magnetic resonance spectroscopy (1 H-NMR).

The active ingredients are suitable for combating parasitic protozoa, which occur in animal husbandry and animal breeding in useful, breeding, zoo, laboratory, experimental and hobby animals, with favorable warm-blooded toxicity. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive strains. By fighting the parasitic protozoa, disease, deaths and reduced performance (e.g. in the production of

Meat, milk, wool, skins, eggs, honey, etc.) can be reduced so that by the use of the active ingredients a more economical and easier animal husbandry is possible.

The parasitic protozoa include:

Mastigophora (Flagellata) such as Trypanosomatidae e.g. Trypanosoma b. brucei, T.b. gambiense, T.b. rhodesiense, T. congolense, T. cruzi, T. evansi, T. equinum, T. lewisi, T. percae, T. simiae, T. vivax, Leishmania brasiliensis, L. donovani, L. tropica, e.g. Trichomonadidae e.g. Giardia lamblia, G. canis.

Sarcomastigophora (Rhizopoda) such as Entamoebidae e.g. Entamoeba histolytica, Hartmanellidae e.g. Acanthamoeba sp., Hartmanella sp.

Apicomplexa (Sporozoa) such as Eimeridae e.g. Eimeria acervulina, E. adenoides, E. alabahmensis, E. anatis, E. anseris, E. arloingi, E. ashata, E. auburnensis, E. bovis, E. brunetti, E. canis, E. chinchillae, E. clupearum , E. columbae, E. contorta, E. crandalis, E. debliecki, E. dispersa, E. ellipsoidales, E. falciformis, E. faurei, E. flavescens, E. gallopavonis, E. hagani, E. intestinalis, E. iroquoina, E. irresidua, E. labbeana, E. leucarti, E. magna, E. maxima, E. media, E. meleagridis, E. meleagrimitis, E. mitis, E. necatrix, E. ninakohlyakimovae, E. ovis, E. parva, E. pavonis, E. perforans, E. phasani, E. piriformis, E. praecox, E. residua, E. scabra, E. spec, E. stiedai, E. suis, E. tenella, E. truncata, E. truttae, E. zuernii, Globidium spec, Hammon dia heyderni, Isospora belli, I. canis, I. felis, I. ohioensis, I. rivolta, I. spec, I. suis, Neospora spec, Neospora carinum, Neospora hugesi, Neospora caninum, Cystisospora spec., Cryptosporidium spec. such as Toxoplasmadidae e.g.

Toxoplasma gondii such as Sarcocystidae e.g. Sarcocystis bovicanis, S. bovihominis,

S. neurona, S. ovicanis, S. ovifelis, S. spec, S. suihominis such as Leucozoidae e.g.

Leucozytozoon simondi, such as Plasmodiidae e.g. Plasmodium berghei, P. falciparum.

P. malariae, P. ovale, P. vivax, P. spec, such as Piroplasmea e.g. Babesia argentina, B. bovis, B. canis, B. spec, Theileria parva, Theileria spec. like Adeleina e.g.

Hepatozoon canis, H. spec. Furthermore Myxospora and Microspora eg Glugea spec. Nosema spec.

Furthermore Pneumocystis carinii, as well as Ciliophora (Ciliata) such as e.g. Balantidium coli, Ichthiophthirius spec., Trichodina spec., Epistylis spec.

The compounds according to the invention are also active against protozoa which occur as parasites in insects. Parasites of the Microsporida strain, in particular of the genus Nosema, may be mentioned as such. Nosema apis is particularly worth mentioning for the honeybee.

Livestock and breeding animals include mammals such as Cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon, birds such as Chickens, geese, turkeys, ducks, pigeons, bird species for home and zoo keeping. It also includes farm and ornamental fish.

Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.

The pets include dogs and cats.

The fish include utility, breeding, aquarium and ornamental fish of all ages that live in fresh and salt water. Useful and farmed fish include e.g. Carp, eel, trout, white fish, salmon, bream, roach, rudd, chub, sole.

Plaice, halibut, Japanese yellowtail (Seriola quinqueradiata), Japanaal (Anguilla japonica), Red seabream (Pagurus major), Seabass (Dicentrarchus labrax). Gray mullet (Mugilus cephalus), Pompano, Gilthread seabream (Sparus auratus). Tilapia spp., Chichlid species such as e.g. Plagioscion, Channel catfish. The agents according to the invention are particularly suitable for the treatment of fish fry, e.g. Carp of

2 to 4 cm body length. The agents are also very suitable for eel fattening. The application can be prophylactic as well as therapeutic.

The active ingredients are used directly or in the form of suitable preparations enterally, parenterally, dermally, nasally.

The enteral application of the active ingredients takes place e.g. orally in the form of powder, suppositories, tablets, capsules, pastes, drinkers, granules, drenches, boluses, medicated feed or drinking water. The dermal application happens e.g. in the form of diving (dipping), spraying (spraying), bathing, washing, pouring on

(pour-on and spot-on) and powdering. Parenteral use happens e.g. in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants.

Suitable preparations are:

Solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on formulations, gels;

Emulsions and suspensions for oral or dermal use and for injection; Semi-solid preparations;

Formulations in which the active ingredient is processed in an ointment base or in an oil in water or water in oil emulsion base;

Solid preparations such as powders, premixes or concentrates, granules, pellets. Tablets, boluses, capsules; Aerosols and inhalants, molded articles containing active ingredients.

Solutions for injection are administered intravenously, intramuscularly and subcutaneously. Injection solutions are prepared by dissolving the active ingredient in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives. The solutions are sterile filtered and filled.

The following may be mentioned as solvents: physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof.

If appropriate, the active compounds can also be dissolved in physiologically tolerable vegetable or synthetic oils which are suitable for injection.

The following may be mentioned as solubilizers: solvents which promote the dissolution of the active ingredient in the main solvent or prevent its precipitation. examples are

Polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol.

Oral solutions are applied directly. Concentrates are used orally after previous dilution to the application concentration. Oral solutions and concentrates are prepared as described above for the injection solutions, and sterile work can be dispensed with.

Solutions for use on the skin are dripped on, spread on, rubbed in, sprayed on, sprayed on or by dipping (dipping). Bathe or wash applied. These solutions are prepared as described above for the injection solutions. It may be advantageous to add thickeners during manufacture. Thickeners are: inorganic thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates.

Gels are applied to, or spread on, or placed in body cavities. Gels are produced by adding enough thickening agent to solutions which have been prepared as described for the injection solutions to form a clear mass with an ointment-like consistency. The thickeners specified above are used as thickeners.

Pour-on formulations are poured onto or sprayed onto limited areas of the skin, the active ingredient either penetrating the skin and acting systemically or being distributed over the surface of the body.

Pour-on formulations are prepared by dissolving, suspending or emulsifying the active ingredient in suitable skin-compatible solvents or solvent mixtures. If necessary, other auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers and adhesives are added.

The following may be mentioned as solvents: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol, mono-butyl glycol, mono Acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethyl acetamide, N-methyl pyrrolidone, 2-dimethyl-4-oxy-methylene-l, 3-dioxolane.

Dyes are all dyes approved for use on animals, which can be dissolved or suspended. Resorption-promoting substances are, for example, DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.

Antioxidants are sulfites or metabisulfites such as potassium metabisulfite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.

Light stabilizers are e.g. Substances from the class of benzophenones or novantisolic acid.

Adhesives are e.g. Cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.

Emulsions can be used orally, dermally or as injections.

Emulsions are either water in oil or oil in water.

They are produced by dissolving the active ingredient either in the hydrophobic or in the hydrophilic phase and, with the aid of suitable emulsifiers and, if appropriate, other auxiliaries such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers and viscosity-increasing agents

Substances homogenized with the solvent of the other phase.

The following may be mentioned as hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid biglyceride, triglyceride mixture with vegetable fatty acids

Chain length Cg.12 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated, possibly also hydroxyl-containing fatty acids. Mono- and diglycerides of Cg / Cj o fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate. Hexyl laurate. Dipropylene glycol pelargonate, ester of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length Cjg-Cjg, isopropyl myristate, Isopropylpalmi- did caprylic / Caprinsäureester of saturated fatty alcohols of chain length _Ci2-C], oleyl oleate, decyl oleate, ethyl oleate, Milchsäureethyl- esters, wax-like fatty acid ester such as dibutyl phthalate, diisopropyl adipate, related to the latter Estergemische ia fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids such as Oleic acid and its mixtures.

The following can be mentioned as the hydrophilic phase:

Water, alcohols such as e.g. Propylene glycol, glycerin, sorbitol and their mixtures.

The following may be mentioned as emulsifiers: nonionic surfactants, e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;

ampholytic surfactants such as di-Na-N-lauryl-β-iminodipropionate or lecithin;

anionic surfactants, such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt; cationic surfactants such as cetyltrimethylammonium chloride.

The following may be mentioned as further auxiliaries: substances which increase viscosity and stabilize the emulsion, such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, and polyacrylates. Alginates, gelatin, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride. Polyethylene glycols. Waxes, colloidal silica or mixtures of the listed substances. Suspensions can be used orally, dermally or as an injection. They are produced by suspending the active ingredient in a carrier liquid, optionally with the addition of further auxiliaries such as wetting agents, dyes, substances that require absorption, preservatives, antioxidants, light stabilizers.

All homogeneous solvents and solvent mixtures may be mentioned as carrier liquids.

The surfactants specified above may be mentioned as wetting agents (dispersants).

Further additives mentioned are those mentioned above.

Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only in their higher viscosity.

To prepare solid preparations, the active ingredient is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and brought into the desired shape.

All physiologically compatible solid inert substances may be mentioned as carriers. All of these serve inorganic and organic substances. Inorganic substances are e.g. Table salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, phosphates.

Organic substances are e.g. Sugar, cellulose, food and feed such as milk powder, animal meal, cereal flour and meal, starches.

Excipients are preservatives, antioxidants, dyes, which have already been listed above. Other suitable auxiliaries are lubricants and lubricants such as, for example, magnesium stearate, stearic acid, talc, bentonite, substances which require decay, such as starch or cross-linked polyvinylpyrrolidone, binders such as, for example, starch, gelatin or linear polyvinylpyrrolidone, and dry binders such as microcrystalline

Cellulose.

The active substances can also be present in the preparations as a mixture with synergists or with other active substances.

Mixtures of the compounds according to the invention with a polyether antibiotic or a synthetically produced coccidiosis agent should be particularly emphasized.

The following may be mentioned as synthetic coccidiosis or as polyether antibiotics for use in the mixtures according to the invention:

Amprolium, partly in combination with folic acid antagonists

Robenidine toltrazuril

Monensin

Salinomycin

Maduramicin

Lasalocid Narasin

Semduramicin.

The mixture with maduramicin should be particularly emphasized.

Ready-to-use preparations contain the active ingredients in concentrations of

10 ppm to 20 percent by weight, preferably from 0.1 to 10 percent by weight. Preparations which are diluted before use contain the active ingredient in concentrations of 0.5 to 90 percent by weight, preferably 1 to 50 percent by weight.

In general, it has proven to be advantageous to administer amounts of about 0.5 to about 50 mg, preferably 1 to 20 mg, of active ingredient per kg of body weight per day in order to achieve effective results.

In a mixture with other coccidiosis agents or polyether antibiotics, the active compounds according to the invention are present in a ratio of 1 to 0.1-10 to 1 to 1-10. The ratio 1 to 5 is preferred.

The active ingredients can also be administered together with the animal's feed or drinking water.

Feed and food contain 0.01 to 250 ppm, preferably 0.5 to 100 ppm of the active ingredient in combination with a suitable edible material.

Such feed and food can be used for medicinal purposes as well as for prophylactic purposes.

Such feed or food is produced by mixing a concentrate or a premix containing 0.5 to 30%, preferably 1 to 20% by weight of an active ingredient in admixture with an edible organic or inorganic carrier with conventional feed. Edible carriers are, for example, corn flour or corn and soybean flour or mineral salts, which preferably contain a small amount of an edible dust-preventing oil, for example corn oil or soybean oil. The premix obtained in this way can then be added to the complete feed before it is fed to the animals. An example of use in coccidiosis is:

For the healing and prophylaxis of, for example, coccidiosis in poultry, especially in chickens, ducks, geese and turkeys, 0.1 to 100 ppm, preferably 0.5 to 100 ppm, of an active ingredient with a suitable edible material, e.g. a nutritious feed, mixed. If desired, these amounts can be increased, especially if the active ingredient is well tolerated by the recipient. Accordingly, the administration can take place via the drinking water.

For the treatment of individual animals, e.g. in the case of the treatment of coccidiosis in mammals or toxoplasmosis, amounts of active compound of 0.5 to 100 mg / kg body weight are preferably administered daily in order to achieve the desired results. Nevertheless, it may be necessary at times to deviate from the amounts mentioned, in particular depending on the body weight of the test animal or the type of administration method, but also because of the

Animal species and its individual response to the active ingredient or the type of formulation and the time or interval at which it is administered. In some cases it may be sufficient to make do with less than the minimum quantity mentioned above, while in other cases the above upper limit must be exceeded. When administering larger quantities, it may be advisable to divide them into several individual administrations during the day.

The effectiveness of the compounds according to the invention can e.g. in cage experiments with the following experimental setup, in which the animals are treated with the respective individual components and with the mixtures of the individual components.

A feed containing active ingredient is prepared in such a way that the required amount of active ingredient is fed with a nutritionally balanced animal feed. eg thoroughly mixed with the chick feed specified under. If a concentrate or a premix is to be prepared, which is ultimately to be diluted in the feed to the values mentioned in the experiment, generally about 1 to 30%, preferably about 10 to 20% by weight of active ingredient with an edible organic or inorganic carrier , for example corn and soy flour or mineral salts, which contain a small amount of an edible defatting oil, for example corn oil or soybean oil. The premix thus obtained can then be added to the whole poultry feed prior to administration.

The following composition is an example of the use of the substances according to the invention in poultry feed.

52.00% feed grain meal, namely: 40% corn, 12% wheat

17.00% soybean meal extr.

5.00% corn gluten feed

5.00% wheat feed flour

3.00% fish meal

3.00% mineral mixture

3.00% alfalfa grass green flour

2.50% vitamin premix

2.00% wheat germ, crushed

2.00% soybean oil

2.00% meat bone meal

1.50% whey powder

1.00% molasses

1.00% brewer's yeast, bound to beer spent grains

100.00%

Such feed contains 18% crude protein, 5% crude fiber, 1% Ca, 0.7% P as well as 1200 iE vitamin A, 1200 iE vitamin D3, 10 mg vitamin E, 20 mg zinc bacitracin per kg.

Preparation Examples Compounds of Formula (I)

example 1

3.3 g (10 mmol) of 4-bromo-2,6-bis-trifluoromethylbenzimidazole are placed in 100 ml of methylene chloride and 1.73 ml (12.5 mmol) of triethylamine are added at 20 ° C. 2.4 g (12.5 mmol) of 4-bromomethyl-5-methyl-1,3-dioxol-2-one in 10 ml of methylene chloride are then added dropwise at 20 ° C. and the mixture is refluxed for 24 hours. The methylene chloride solution is washed 3 times with 30 ml of water each time, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (35-70 μm) with cyclohexane / ethyl acetate (3: 1). 1.5 g (34% of theory) of the above compound are obtained. Mp: 141-143 ° C.

Examples 2 to 28 were obtained analogously to Example 1 and in accordance with the general information on the preparation.

Preparation of the starting compound for Example 14

Example a)

1,400 g (6.7 mol) of 2,3-tetrafluoro-l, 4-benzodioxane and 7 g (0.08 mol) of FeS (powder) are initially introduced, dripped at 20 to 30 ° C. in about 4 h 1 190 g (7.4 mol) of bromine are added and the mixture is stirred for about 20 h until the evolution of gas has ended. It is washed with aqueous sodium sulfite solution and dried over sodium sulfate. The residue is distilled in vacuo.

Yield: 1 540 g (80% of theory), KplO: 70-74 ° C (GC: 99%).

Example b)

350 g (1.2 mol) 6-bromo-2,3-tetrafluoro-1,4-benzodioxane are added dropwise at 20 ° C. in 75 min to 273 ml (98%) nitric acid and 293 ml conc. Sulfuric acid, stirring for 1 h at 20 ° C and 3 h at 40 ° C. The batch is poured onto ice, extracted with methylene chloride, the organic phase is washed with water, with aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. The organic phase is evaporated and further converted as a crude product. Yield: 396 g (98% of theory), (crude, GC: 99.1%), Kpl6: 121-124 ° C, nD: 1.5065 at 20 ° C.

Example c)

396 g (1.2 mol) of 6-bromo-7-nitro-2,3-tetrafluoro-1,4-benzodioxane are placed in 1,400 ml of ethanol, 253 g (4.5 mol) of Fe powder are added and heated to reflux. Then 29 g of conc. Hydrochloric acid and stir for 1 h, drips in the

Heat to 43 ml of water and stir for 2 h. The mixture is cooled, the precipitate is filtered off with suction and washed with ethanol. The mother liquor is made alkaline and evaporated. The residue is taken up in methylene chloride and washed twice with water and dried over sodium sulfate. The organic phase is evaporated.

Yield: 313 g (87% of theory), (GC: 95.3%).

Example d)

313 g (1.04 mol) of 7-amino-6-bromo-2,3-tetrafluoro-1,4-benzodioxane are placed in 1250 ml of toluene and 500 g (4.4 mol) of trifluoroacetic acid and added in portions at 20 to 25 ° C 188 g (1.3 mol) of phosphorus pentoxide. The approach becomes lumpy. The mixture is heated at 80 ° C. for 1 h (not stirrable). 500 ml of water are added and the mixture is stirred at 80 ° C. for 1 h. After cooling, the organic phase is separated off and dried over sodium sulfate. The evaporated residue (340 g) still contains 50% educt (GC).

The residue (340 g, 50% strength) is therefore mixed again with 1250 ml of toluene and 500 g (4.4 mol) of trifluoroacetic acid, then 188 g (1.3 mol) of phosphorus pentoxide are added in portions and the mixture is heated to 80 ° C. for 5 h heated. The organic phase is decanted off, washed twice with water, dried over sodium sulfate and evaporated.

Yield: 273 g (66% of theory), mp: 79-81 ° C. (GC: 98%)

The lumpy reaction residue is mixed with water, the organic portion is separated off, dried over sodium sulfate and evaporated.

Yield: 56 g (14%), (GC 87%).

Example e)

273 g (0.7 mol) of 6-bromo-7-trifluoromethylcarbonylamino-2,3-tetrafluoro-1,4-benzodioxane are placed in 2047 ml of conc. Sulfuric acid before and 300 g of mixed acid are added dropwise at 0 ° C. in 15 min and 1000 ml of methylene chloride are added to the thick slurry at 0 to 20 ° C. The solution is then stirred at 40 ° C for 2 h. The cooled contents of the flask are poured onto ice water and the precipitate is isolated. The organic phase is separated from the mother liquor and dried over sodium sulfate. The evaporated residue and the isolated precipitate are combined. Yield: 269 g (88% of theory), mp: 158-159 ° C. (GC: 100%).

Example f

347 g (0.8 mol) of 6-bromo-8-nitro-7-trifluoromethylcarbonylamino-2,3-tetrafluoro-l, 4-benzodioxane are placed in 1735 ml of ethanol and 183 g (3.3 mol) of Fe- Chips and 183 g (3.3 mol) of Fe powder. 38.5 ml of hydrochloric acid are added dropwise under reflux, the mixture is stirred for 1 hour, then 58 ml of water are added dropwise and the mixture is refluxed for 15 hours. The cooled batch is suctioned off, the mother liquor is made alkaline and evaporated. The residue is taken up in methylene chloride, washed twice with water, dried over sodium sulfate and evaporated. The residue (170 g) is chromatographed on 1 kg of silica gel (35-70 μm) with cyclohexane / ethyl acetate (5: 1). Yield: 125 g (40% of theory), mp 162-164 ° C.

Biological examples

Cage trial coccidiosis / chick

Male chicken chicks raised 8 to 12 days old without coccidia (e.g.

LSL Brinkschulte / Senden) receive the compounds (test substances) according to the invention (test substances) in the concentration indicated in ppm with the feed from 3 days before (day -3) the infection (= a.i.) to 8 (9) days after the infection (= p.i.). 3 animals are kept in each cage. One to several such groups are used per dosage. The infection occurs directly in the throat by means of a pharynx

Goiter with about 100,000 spotted oocysts from Eimeria acervulina, each with about 30,000 oocysts from E. maxima and 40,000 spotted oocysts from E. tenella. These are highly virulent strains. The exact dose of infection is set so that one of three experimentally infected untreated chicks dies as a result of infection. The following criteria are taken into account for the evaluation of the effectiveness: weight gain from the start of the test to the end of the test, infection-related death rate, macroscopic evaluation of the faeces with regard to diarrhea and blood excretion on days 5 and 7 pi (evaluation 0 to 6), macroscopic evaluation of the intestinal mucosa, especially the appendix (Rating 0 to 6) and the oocyst excretion and the proportion (in%) of the oocysts sporulating within 24 hours. The number of oocysts in the faeces was determined with the help of the McMaster counting chamber (see Engelbrecht and co-workers "Parasitological working methods in medicine and veterinary medicine, Akademie-Verlag, Berlin (1965)). The individual findings are compared to the untreated, uninfected control Groups were set and an overall rating was calculated (cf. A. Haberkorn (1986), pp. 263 to 270 in Research in Avian Coccidiosis ed LR McDougald, LP Joyner, PL Long Proceedings of the Georgia Coccidiosis Conference Nov. 18-20, 1985 Athens / Georgia UNITED STATES). Experimental results with combinations according to the invention are listed as examples in the following tables. The synergistic effectiveness of the combinations compared to the individual components is particularly evident in the reduction in oocyst excretion, but also in terms of the section findings, weight development and better tolerance.

In the following tables in the "Treatment" column, n.inf.contr. = uninfected control group inf.contr. = infected control group 1 = benzimidazole Example No.

The "ppm" column shows the concentration of the active ingredient used in the feed in ppm.

In the "mortality" column, the percentage of deaths is given under%

Animals and under n the number of animals died / animals used in the experiment.

The column "weight% of not inf. Control" shows the ratio of the weight of the treated animals to the weight of the non-infected control group.

In the "dropping scores", "lesion score" and "oocyst control" columns, details of the effect are given.

The overall rating is rated in the "% efficacy"column; 0% means no effect, 100% means full effect. The results of the activity tests with the compounds according to the invention are summarized in the following table:

Table 1

Efficacy against Eimeria acervulina, Eimeria maxima and Eimeria tenella

Evaluation scheme: 2 = full effect

1 = weak effect 0 = ineffective T = death

Table 4:

Experimental infection with Eimeria acervulina, Eimeria maxima and Eimeria tenella in chicks. Example 15

Table 5:

Experimental infection with Eimeria acervulina, Eimeria maxima and Eimeria tenella in chicks. Example 28

Table 6:

Experimental infection with Eimeria acervulina, Eimeria maxima and Eimeria tenella in chicks. Example 18

Table l l:

Experimental infection with Eimeria acervulina, Eimeria maxima and Eimeria tenella in chicks. Example 14 in combination with Maduramicin

Table 12:

Experimental infection with Eimeria acervulina, Eimeria maxima and Eimeria tenella in chicks. Example 11 in combination with Maduramicin

Claims

claims

1. Benzimidazoles of the formula (I)

in which

R ^{1 represents} fluoroalkyl,

R ^{2 represents} hydrogen or alkyl,

R ^{3 represents} alkyl,

X ¹ , X ² , X ³ and X ⁴ independently of one another represent hydrogen, halogen, haloalkyl, haloalkoxy, haloalkylthio or haloalkylsulfonyl,

or

X ² and X ³ or X ³ and X ³ together represent a dioxyhaloalkylene.

2. A process for the preparation of compounds according to claim 1 of the formula

(I)

in which

R ¹ , R ² , R ³ , X ¹ to X ^{4 have} the meanings given in Claim 1, characterized in that 1 H-benzimidazoles of the formula (II)

in which

R ¹ and X ¹ to X ^{4 have} the meaning given in claim 1,

with an alkylating agent of formula (III)

in which

A stands for a suitable leaving group,

R ² and R ^{3 have} the meaning given in claim 1,

if appropriate in the presence of diluents and / or reaction auxiliaries.

3. Agent, characterized by a content of at least one compound of formula (I) according to claim 1.

4. Use of compounds of formula (I) according to claim 1 for combating parasites.

5. A method of combating parasites, characterized in that compounds of the formula (I) according to Claim 1 are allowed to act on parasites.

6. A process for the preparation of antiparasitic agents, characterized in that compounds of the formula (I) according to Claim 1 are mixed with extenders and / or surface-active agents.

7. Use of compounds of formula (I) according to claim 1 for the preparation of antiparasitic agents.